Henri Rochefort is a French biochemical doctor, born on 20 November 1935 in Paris, who studied the influence of various hormones and their antagonists on breast and ovarian cancers. He is a corresponding member of the French Academy of sciences.
Biography Training He was born on 20 November 1935 in Paris to Fernande Bernhart, a decorator and Marcel Rochefort, a photographer.
After secondary studies in Paris (lycée Carnot) where he became a laureate of the Concours Général des lycées en Sciences Naturelles, he followed a university education with a doctorate in medicine in 1968, a licence ès sciences in 1965, a doctorat ès sciences 3e cycle endocrinologie- in 1966, then a doctorat ès sciences in 1972.
He was a medical intern in the Paris hospitals in the 1961 competition in clinical endocrinology departments and trained in research as an associate and then as a research fellow in Étienne-Émile Baulieu's Inserm Unit from 1964 to 1970.
Career He was recruited at the Faculty of Medicine of Montpellier as Associate Professor, Hospital Biologist in 1970, then Professor of Biochemistry in 1981, then as Professor of Cell Biology from 1984 to 2004, and finally Professor Emeritus since 2005.
As a hospital biologist, (1970-2001) he developed assays for steroid hormones, hormone receptors and prognostic and predictive tissue markers for response to targeted therapies in breast cancer. He continues his research as founding director of Unit 148 of the Inserm Cellular and Molecular Endocrinology Unit and then Hormones and Cancers Unit (1970-2000).
He is married and has 3 children.
Main scientific contributions Rochefort's scientific work has focused on the influence of sex steroid hormones and their antagonists in breast and ovarian cancer.
1. Pharmacology of sex steroid receptors. Some androgens are estrogenic when they interact with estrogen receptors (ER) (1-3). As early as 1972, Henri Rochefort showed that antiestrogens inhibit tumor growth via ERs, which then facilitated their routine use in the treatment of positive ER breast cancers. Discovery of a metabolite with a high affinity for RE, 4-hydroxytamoxifen, which is produced in vivo and accumulated in RE positive cancers. A mutation of the enzyme activating tamoxifen by hydroxylation is responsible for some innate tamoxifen resistance in patients treated for breast cancer. Antiestrogens also inhibit the effect of growth factors in the absence of estrogens. RU 486, a progesterone antagonist, inhibits the growth of breast cancer via the progesterone receptor, suggesting the value of anti-progestins for the treatment of antiestrogen-resistant breast cancers expressing this receptor.
2. By specifying the mechanism of estrogen mitogenic action in breast cancer lines, Henri Rochefort and his team discovered cathepsin D as an actor in tumor progression. (17-33) As early as 1980, H. Rochefort with F Vignon introduced the notion of autocrine regulation by mitogenic factors secreted and induced by estrogens.F. Vignon et al., « Endocrinologie. Les protéines œstrogéno-induites sécrétées par les cellules mammaires cancéreuses humaines MCF7 stimulent leur prolifération », Comptes Rendus de l'Académie des Sciences, 296, (1983)., p. 151-156D. Chalbos, et al., « Estrogens stimulate cell proliferation and induce secretory proteins in a human breast cancer cell line (T47D) », Journal of Clinical Endocrinology and Metabolism, 55, (1982), p. 276-283 He focused the activity of his research unit on a 52 kilo-dalton glycoprotein, induced by estrogens and growth factors; secreted in excess by breast cancer cells and endowed with autocrine mitogenic activity.B. Westley and H Rochefort, « A secreted glycoprotein induced by estrogen in human breast cancer cell lines », Cell, 20, (1980), p. 352-362M. Morisset, F. Capony, H. Rochefort, « The 52-kDa estrogen-induced protein secreted by MCF7 cells is a lysosomal acidic protease », Biochemical and Biophysical Research Communications, 138, (1986), p. 102-109F Capony et al., « Phosphorylation, glycosylation and proteolytic activity of the 52kD estrogen-induced protein secreted by MCF7 cells », Journal of Cellular Biology, 104, (1987), p. 253-262H. Rochefort et al., « Estrogen-induced lysosomal proteases secreted by breast cancer cells. A role in carcinogenesis ? », Journal of Cellular Biochemistry, 35, (1987), p. 17-29P. Augereau et al., « Cloning and sequencing of the 52K cathepsin D cDNA of MCF7 breast cancer cells and mapping on chromosome 11 », Molecular Endocrinology, 2, (1988)., p. 186-192H. Rogier et al., « Two-site immuno-enzymometric assay for the 52-kDa-cathepsin D cytosols of breast cancer tissues », Clinical Chemistry, 35, (1989), p. 81-85S Thorpe, H. Rochefort et al., « Association between high concentrations of Mr 52,000 cathepsin-D and poor prognosis in primary human breast cancer », Cancer Research, 49, (1989), p. 6008-6014F. Spyratos, et al., « Cathepsin D: An independent prognostic factor for metastasis of breast cancer », The Lancet, ii, 8672, (1989), p. 1115-1118F. Capony et al., « Increased secretion and altered proces¬sing and glycosylation of pro-cathepsin D in human mammary cancer cells », Cancer Research, 49, (1989), p. 3904-3909V. Cavailles, M. Garcia, H. Rochefort, « Regulation of cathepsin D and pS2 gene expression by growth factors in MCF7 human breast cancer cells », Molecular Endocrinology, 3, (1989), p. 552-558H. Rochefort et al., « Cathepsin D in breast cancer: From molecular and cellular biology to clinical applications », Cancer Cells (Cold Spring Harbor NY), 2, (1990), p. 383-388M. Garcia, D. Deroccq, P. Pujol, H. Rochefort, « Overexpression of transfected cathepsin D in transformed cells increases their malignant phenotype and metastatic potency », Oncogene, 5, (1990), p. 1809-1814V. Cavailles, P. Augereau, and H Rochefort, « Cathepsin D gene is controlled by a mixed promoter and estrogens stimulate only TATA dependent transcription in breast cancer cells », Proceedings of the National Academy of Sciences USA, 90, (1993), p. 203-207P. Roger et al., « Dissociated overexpression of cathepsin D and estrogen receptor alpha in preinvasive mammary tumors », Human Pathology, 3, (2000), p. 593-600M Glondu et al., « Down-regulation of cathepsin D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells », Oncogene, 21, (2002), p. 5127-5134 With monoclonal antibodies, developed with Sanofi, an assay of 52 K protein in breast cancer extracts in several retrospective double-blind studies showed in a totally unexpected way that high concentrations of this protein in the primary tumor predicted the subsequent development of clinical metastases (an example of serendipity).
The 52k protein was then identified as the precursor of cathepsin D (cathept D) a lysosomal protease diverted into the extracellular matrix.
Henri Rochefort has clarified the mechanism of its transcriptional regulation by estrogens and its deregulation in breast cancers leading to its secretion. Pro cath D acts, depending on the pH of the extracellular tumor medium, as a protease or as the ligand of a membrane receptor to facilitate the survival and growth of micro-metastases that have escaped from the tumor before its removal. After confirmation in many Centres around the world, Cathedral D has become the first example of a protease, the measurement of which in the primary tumor has a prognostic value. Its overexpression after transfection of the D-cath gene into tumor cells increases their metastatic power in athymic mice. Conversely, the inhibition of its production by transfection of anti-sense RNA into breast cancer cells inhibits their growth and metastatic power in these mice. (29-32) Thus, cath D is a potential therapeutic target for breast cancers, mainly triple-negative cancersH Rochefort et al., « How to target estrogen receptor-negative breast cancer? », Endocrine Related Cancer, 10, (2003), p. 261-266 as well as other solid tumors that overexpress it, such as colorectal cancer and melanoma.
3. Other novel pathways have been opened, such as transcriptional interference between RE and transcriptional factors (AP1),A. Philips, D. Chalbos, H. Rochefort, « Estradiol increases and antiestrogens antagonize the growth factor-induced activator protein-1 activity in MCF7 breast cancer cells, without affecting c-fos and c-jun synthesis », Journal of Biological Chemistry, 268, (1993), p. 14103-14108 and variations in tissue expression by immunohistochemistry of ovarian hormone receptors (including estrogen beta receptor) in pre-cancerous breast lesions. Fibulin 1, induced by estrogens, is secreted in excess by ovarian cancer cells and accumulated in vivo in the extracellular matrix.G. Clinton, et al., « Estrogens increase the expression of fibulin 1, an extracellular matrix protein, secreted by human ovarian cancer cells », Proceedings of the National Academy of Sciences USA, 93, (1996), p. 316-320P. Roger et al., « Increased immunostaining of fibulin-1, an estrogen-regulated protein in the stroma of human ovarian epithelial tumors », American Journal of Pathology, 153, (1998), p. 1579-1588 Progestogen-induced fatty acid synthase (also a potential therapeutic target.H.Rochefort, D. Chalbos, «Progestin-specific Markers in Human Cell Lines: Biological and Pharmacological Applications», Molecular and Cellular Endocrinology, 36, (1984), p. 3-10S. Bardon, F. Vignon, D. Chalbos, H Rochefort, « RU486, a progestin and glucocorticoid antagonist inhibits the growth of breast cancer cells via the progesterone receptor », The Journal of Clinical Endocrinology and Metabolism, 60, (1985), p. 692-697D. Chalbos et al., « Fatty acid synthetase and its mRNA are induced by progestin in breast cancer cells », Journal of Biological Chemistry, 262, (1987), p. 9923-9926D. Chalbos et al., « Expression of the progestin-induced fatty acid synthetase in benign mastopathies and breast cancer as measured by RNA in situ hybridization », Journal of the National Cancer Institute, 82, (1990), p. 602-606 Its early overexpression may partly explain the increase in breast cancer incidence by progestins in women treated for menopause.
Hypersensitivity to estrogens in "at risk" breast lesions may be due to a decrease in the estrogen beta receptor.P.Roger, J.A.Gustafson, et al., « Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors», Cancer Research, 61, (2001), p. 2537-2541
In total, starting from fundamental research on human breast cancer lines and after having prepared original specific molecular probes, H. Rochefort has transferred some of his results to the clinic and contributed internationally to the understanding of the mechanisms of hormonal carcinogenesis and to the therapeutic management of breast and ovarian cancers.
4. Since 2000, as Professor Emeritus of Cell Biology and Member of the National Academies of Medicine and Science,
As research was no longer funded in France after retirement, Henri Rochefort reoriented himself towards general topics more directly useful in public health by leading several working groups.